The rapid development of antibiotics is of great significance in modern medical history. Penicillin is the first β-lactam antibiotics that is successfully used in clinic, and provides an important direction for massive application of β-lactam type antibiotics in clinic. The β-lactamases generated in cells are capable of hydrolyzing antibiotics having a β-lactam ring structure and inactivating the antibiotics, which is the most common mechanism of bacterial resistance to β-lactam antibiotics. According to differences of amino acid sequences in molecular structure. β-lactamases can be divided into two main groups: one group including A, C and D types with serine as active site, and another group including metalloenzymes with metal ions (especially Zn2+ ion) as active sites.
With the massive application of β-lactam type antibiotics, the resistance to β-lactam type antibiotics mediated by β-lactamase has become increasingly serious.
There are two thoughts in developing β-lactamase inhibitors: (1) developing a substrate of β-lactamase, reversibly/irreversibly binding to affinity site of enzyme to amidate β-lactamase, so as to enable an antibiotic co-administrated with the substrate of β-lactamase to exert effects: (2) developing a “suicide enzyme inhibitor” with relevant mechanism or being irreversible, reacting with β-lactamase to form a non-covalent Michaelis complex, incurring a serine nucleophilic attack on amido bond to open D-lactam ring, then rearrangement and so on to inactive enzyme, in which its structure is destroyed as well, and thus it is also called as suicide enzyme inhibitor.
The β-lactamase inhibitors successfully used in clinic include Clavulanic acid. Sulbactam and Tazobactam, which structures are shown as follows:

Clavulanic acid was firstly separated from Streptomyces clavuligerus in 1970. It has a slight antibacterial activity when used alone, but it can significantly reduce minimal inhibitory concentrations of amoxicillin against K. pneumonia, Proteus mirabilis and E. coli when combined with amoxicillin. Its main enzyme spectrum is for type A β-lactamases (CTX-M, TEM-1, SHV-1, KPC, etc.), but it shows poor combination effects on resistances induced by type B metalloenzymes (IMP, NDM-1, VIM, etc.), type C enzymes (AmpC, etc.), type D enzymes (OXA, etc.) and so on. Sulbactam and Tazobactam are enzyme inhibitors separately developed in 1978 and 1980, which mainly improve inhibitory effects on type C enzymes (AmpC) and type D enzymes (OXA), but they still show poor inhibitory activity on type B metalloenzymes. In the meantime, all of the three enzyme inhibitors are structural analogues of penicillin, belong to irreversible “suicide enzyme inhibitors”, and thus have short action time.
Avibactam is a diazabicyclooctanone compound, which combined with ceftazidime came into the market in the U.S. on Feb. 27, 2015. In comparison with the three β-lactamase inhibitors in the market, it is characterized by long-term of enzyme inhibitory effects, reversible covalent binding to enzyme, and not inducing generation of β-lactamases. However, it still shows poor effects on type B metalloenzymes, which significantly limits its clinical applications. In addition, since Avibactam has a short T1/2 and multiple dosing per day is required, which results in poor compliance in patients, Avibactam does not meet clinical requirements. Like Avibactam, MK-7655 is also a diazabicyclooctanone compound, which combined with Imipenem and Cystatin in phase III clinical trials. Similar to Avibactam, its antienzymatic spectrum is broadened in comparison with the three β-lactamase inhibitors in the market, but it still shows poor pharmaceutical effects on type B metalloenzymes. In addition, its T1/2 in clinic is only 1.7 h, requiring 4 doses per day, which would be its bottleneck in clinical applications as well. The structures of Avibactam and MK-7655 are shown as follows:

Hence, it is a new development hotspot to screen antagonizing drug-resistance β-lactamase inhibitor compounds which have a longer half-life and a low clearance rate and can be used to solve the technical problem associated with bacterial drug-resistance caused by β-lactamase. The compounds of the present invention are characterized by broader antibacterial spectrum, and can act as β-lactamase inhibitors from molecular level perspective and antibacterial agents from cellular perspective.